Bottom Line:
As a consequence of this noncovalent interaction, a global absolute screw sense preference, detectable by (13)C NMR, is induced in the foldamer.Addition of base, or acid, to the mixture of ligands competitively modulates their interaction with the binding site, and reversibly switches the foldamer chain between its left and right-handed conformations.As a result, the foldamer-ligand mixture behaves as a biomimetic chemical system with emergent properties, functioning as a "proton-counting" molecular device capable of providing a tunable, pH-dependent conformational response to its environment.

ABSTRACTBiomolecular systems are able to respond to their chemical environment through reversible, selective, noncovalent intermolecular interactions. Typically, these interactions induce conformational changes that initiate a signaling cascade, allowing the regulation of biochemical pathways. In this work, we describe an artificial molecular system that mimics this ability to translate selective noncovalent interactions into reversible conformational changes. An achiral but helical foldamer carrying a basic binding site interacts selectively with the most acidic member of a suite of chiral ligands. As a consequence of this noncovalent interaction, a global absolute screw sense preference, detectable by (13)C NMR, is induced in the foldamer. Addition of base, or acid, to the mixture of ligands competitively modulates their interaction with the binding site, and reversibly switches the foldamer chain between its left and right-handed conformations. As a result, the foldamer-ligand mixture behaves as a biomimetic chemical system with emergent properties, functioning as a "proton-counting" molecular device capable of providing a tunable, pH-dependent conformational response to its environment.

fig6: Conformational switching of foldamer F4* with competingchiral ligands. [F4*] = 10 mM, CDCl3, 296K; all subsequent additions are of 1.5 equiv relative to F4*. Portions of the 13C NMR spectra of the mixtures containingthe labeled signals of F4* are shown, with anisochronicityΔδ reported as the difference in chemical shift betweenthe major and minor labeled signals of F4*, δmaj – δmin, measured in ppb. Protonatedspecies available for interaction with the F4* bindingsite (represented by the pyridine in the colored rectangle) are indicatedby blue/green (for chiral species) or gray (for achiral species) disks,and acids HA are stacked in order of pKa in CDCl3. The number of protons availableis represented by the number of discs, building up from the bottomof the stack. Proposed conformation-inducing interactions with F4* (whether these are hydrogen-bonded or ion-paired is leftundefined) are coded by matched colors: blue indicates induction ofa P screw-sense; green indicates induction of an M screw-sense; red indicates no screw-sense induction. Themost significant interaction is assumed to be between F4* and the top (typically the most acidic) protonated species in eachmultiply protonated stack.

Mentions:
Now the scene was set for a competitionexperiment70 between two ligands. (S)-HA1 (1.5 equiv) was added to a solutionof F4* (1.0 equiv)in CDCl3 to induce P screw sense (Figure 6a,b) with the anisochronicity +904 ppb characteristicof the ca. 50% h.e. induced in the HA1↔F4 pair (cf. Table 1, entry 4). On additionof the stronger acid (R)-HA4 (1.5 equiv)to the mixture (Figure 6c), the major signalin the 13C NMR spectrum moved upfield of the minor, indicatinga switch in the screw sense preference of F4* from P to M.27,84 The anisochronicityof the signals also increased in magnitude to −945 ppb, suggestingalmost exclusive formation of a paired (R)-HA4↔F4* ligand-foldamer complex (Table 1, entry 4). Evidently, HA4 can completelydisplace HA1 from the pyridyl binding site, a resultthat is most readily understood as a consequence of the tighter pairingbetween the foldamer F4* and the stronger acid HA4.62 In the absence of detailedknowledge about the extent of proton transfer in the acid–basepairs in this and subsequent studies, foldamer F4* isrepresented by a neutral pyridine ring irrespective of its probableprotonation state: it may be assumed that this pyridine pairs withthe most acidic species available, by a mechanism that we leave undefineddiagrammatically.

fig6: Conformational switching of foldamer F4* with competingchiral ligands. [F4*] = 10 mM, CDCl3, 296K; all subsequent additions are of 1.5 equiv relative to F4*. Portions of the 13C NMR spectra of the mixtures containingthe labeled signals of F4* are shown, with anisochronicityΔδ reported as the difference in chemical shift betweenthe major and minor labeled signals of F4*, δmaj – δmin, measured in ppb. Protonatedspecies available for interaction with the F4* bindingsite (represented by the pyridine in the colored rectangle) are indicatedby blue/green (for chiral species) or gray (for achiral species) disks,and acids HA are stacked in order of pKa in CDCl3. The number of protons availableis represented by the number of discs, building up from the bottomof the stack. Proposed conformation-inducing interactions with F4* (whether these are hydrogen-bonded or ion-paired is leftundefined) are coded by matched colors: blue indicates induction ofa P screw-sense; green indicates induction of an M screw-sense; red indicates no screw-sense induction. Themost significant interaction is assumed to be between F4* and the top (typically the most acidic) protonated species in eachmultiply protonated stack.

Mentions:
Now the scene was set for a competitionexperiment70 between two ligands. (S)-HA1 (1.5 equiv) was added to a solutionof F4* (1.0 equiv)in CDCl3 to induce P screw sense (Figure 6a,b) with the anisochronicity +904 ppb characteristicof the ca. 50% h.e. induced in the HA1↔F4 pair (cf. Table 1, entry 4). On additionof the stronger acid (R)-HA4 (1.5 equiv)to the mixture (Figure 6c), the major signalin the 13C NMR spectrum moved upfield of the minor, indicatinga switch in the screw sense preference of F4* from P to M.27,84 The anisochronicityof the signals also increased in magnitude to −945 ppb, suggestingalmost exclusive formation of a paired (R)-HA4↔F4* ligand-foldamer complex (Table 1, entry 4). Evidently, HA4 can completelydisplace HA1 from the pyridyl binding site, a resultthat is most readily understood as a consequence of the tighter pairingbetween the foldamer F4* and the stronger acid HA4.62 In the absence of detailedknowledge about the extent of proton transfer in the acid–basepairs in this and subsequent studies, foldamer F4* isrepresented by a neutral pyridine ring irrespective of its probableprotonation state: it may be assumed that this pyridine pairs withthe most acidic species available, by a mechanism that we leave undefineddiagrammatically.

Bottom Line:
As a consequence of this noncovalent interaction, a global absolute screw sense preference, detectable by (13)C NMR, is induced in the foldamer.Addition of base, or acid, to the mixture of ligands competitively modulates their interaction with the binding site, and reversibly switches the foldamer chain between its left and right-handed conformations.As a result, the foldamer-ligand mixture behaves as a biomimetic chemical system with emergent properties, functioning as a "proton-counting" molecular device capable of providing a tunable, pH-dependent conformational response to its environment.

ABSTRACTBiomolecular systems are able to respond to their chemical environment through reversible, selective, noncovalent intermolecular interactions. Typically, these interactions induce conformational changes that initiate a signaling cascade, allowing the regulation of biochemical pathways. In this work, we describe an artificial molecular system that mimics this ability to translate selective noncovalent interactions into reversible conformational changes. An achiral but helical foldamer carrying a basic binding site interacts selectively with the most acidic member of a suite of chiral ligands. As a consequence of this noncovalent interaction, a global absolute screw sense preference, detectable by (13)C NMR, is induced in the foldamer. Addition of base, or acid, to the mixture of ligands competitively modulates their interaction with the binding site, and reversibly switches the foldamer chain between its left and right-handed conformations. As a result, the foldamer-ligand mixture behaves as a biomimetic chemical system with emergent properties, functioning as a "proton-counting" molecular device capable of providing a tunable, pH-dependent conformational response to its environment.